Slug参与CP-31398介导的p53突变型子宫内膜癌细胞凋亡的机制研究

The poor prognosis of mutant p53 endometrial cancer is still lack of effective therapeutic methods. P53 modulating agent, CP-31398 can significantly target mutant p53 endometrial cancer cells and these effects were positively related to the Slug expression in our previous study. In order to enhance the therapeutic effect, our study involves p53 mutant endometrial carcinoma cells with high sensitivity to CP-31398, intends to dig out the mechanism of Slug involved in CP-31398 reactivation of the function of p53 protein, down regulation of Wnt pathway and apoptosis of tumor cells. In addition, in order to establish the research system of animal tumor model based on individualized treatment, we aimed to establish the specific mutant p53 endometrial cancer patients derived tumor xenografts mouse model to evaluate the relationship between the effectiveness of CP-31398 treatment and the Slug expression. The outcome of our study can provide evidence for the treatment of mutant p53 tumors with CP-31398, reduce the side effects and make a guide to develop the new drugs with lower toxicity or the combination therapy.

目前尚缺乏对p53突变型子宫内膜癌有效的治疗手段，本课题前期研究发现突变p53逆转剂CP-31398能有效抑制p53突变型子宫内膜癌细胞，此干预效果与Slug的表达呈正相关。为了提高其对肿瘤的抑制效果，本研究以对CP-31398敏感性较高的p53突变型子宫内膜癌细胞为研究对象，从机制角度检测Slug参与CP-31398重新激活p53蛋白功能，下调Wnt通路，促进肿瘤细胞凋亡的过程。进而通过建立患者来源的p53突变型子宫内膜癌组织移植（PDTX）小鼠模型，评估CP-31398对Slug差异表达的p53突变型子宫内膜癌干预的有效性，为建立基于个体化治疗的人体肿瘤标本动物模型研究体系奠定基础，从而提高CP-31398对肿瘤患者的治疗效果，降低使用剂量，减少毒副作用。为指导类似低毒性药物的研发，以及低剂量联合其他化疗药物治疗p53突变型肿瘤病人提供依据。

子宫内膜癌以其高发病率著称，其中p53突变型患者预后最差。本研究以p53突变型子宫内膜癌为研究对象，选取p53逆转剂CP-31398，选取我院83份子宫内膜癌标本，并通过构建慢病毒载体建立细胞模型，研究发现Slug可作为CP-31398重新激活p53蛋白功能的关键因子，参与MDM2通路调节MMP-2、MMP-9、p21、Cyt-c等蛋白，上调促凋亡蛋白Puma、Bax的表达，从而杀伤p53突变型子宫内膜癌细胞，并通过裸鼠成瘤实验，针对性的构建了人源性的p53突变型子宫内膜癌PDTX动物模型进行了验证。本研究初步明确了CP-31398的抑癌作用机制，探索了CP-31398的适用人群，为p53突变型子宫内膜癌的治疗提供新的可能。